Toward Safer and More Effective Drugs, Food and Medical Products

by Food and Drug Administration (FDA)

New technologies and tools have been developed as a direct result of the nation's decade-long effort to understand the entire sequence of the molecule that holds the genetic information that makes us who we are.

The effort to decode the sequence of the molecule called deoxyribonucleic acid — DNA for short — is called the Human Genome Project. It is the basis for understanding the blueprint that directs our external appearance, such as hair and eye color, skin color, sex, height, and behavior, as well as the quality of our internal organs.

This special issue of FDA Consumer presents the Food and Drug Administration's response to several of these emerging technologies as they relate to the discovery of and the safety assessment of the food, drugs, biologics, and medical devices it regulates.

The gene is a unit or segment of the DNA that contains the information for a protein, which is a building block or a catalyst in each of our cells. The complete DNA content of our cells, called the human genome, contains many such segments or genes. A gene or set of genes are expressed, that is, function, when there is a need for the building blocks to sustain the life of the organism. In this way, the genome contains the architectural blueprint that dictates each individual's makeup.

The '-Omics' Defined

Humans develop from a single fertilized egg to become a multicellular organism made up of a variety of organs and tissues. The DNA of the human genome contains all the information that prescribes whether a particular cell becomes part of the liver, or part of the brain, kidney, or bone. This comes about mainly through the extremely well-coordinated and differential expression of genes within the particular cell. When this ordered expression of genes goes awry, called perturbed by scientists, diseases such as cancer can result.

Functional Genomics is the study of gene function on a whole or partial genome scale that includes the study of gene expression using DNA microarray technology. It measures the expression of genes under normal and perturbed conditions and attempts to predict the gene expression profiles for these conditions.

Structural Genomics involves identification of genes that predispose people to various diseases, including cancer. Those working in structural genomics also study genes that may alter a person's response to a drug or other substance, resulting in an adverse event. An example of the latter is the recent episode of some patients' reaction to Vioxx (rofecoxib) and other Cox-2 inhibitors. Functional and structural genomics are considered emerging technologies that will help the development of personalized medicine to eventually replace the "one size fits all" approach to medicine.

Proteomics, the protein complement expressed by the genome of an organism, is the global analysis of cellular proteins. Proteins play a role in maintaining the structure of the cell or organism and also can act as enzymes or catalysts converting one molecule into another.

The molecules that are altered by enzymes are termed metabolites. Metabolomics, also called metabonomics, is the study of metabolite profiles in biological samples, in particular urine, saliva, and blood plasma. In some instances, cerebrospinal fluid may be the source for analysis. The Holy Grail of these new technologies is to prove that the study of metabolites can accurately predict gene expression and protein production using only a sample obtained from a patient in a non-invasive way.

Until several years ago, scientists were limited to studying a single gene at a time and to attempting to understand how that gene contributed to the normal physiological status of an organism. Sometimes, the gene studied was chosen because of its importance in specific disease pathways or because the product of that gene, a protein, was a target of a drug that was under development. The data generated were generally small in quantity and could easily be assessed by the person developing the hypothesis to try to understand how the gene works.

Today, however, scientists have the capacity to simultaneously study all the expressed genes in an organism. In humans, there are about 30,000 genes that can be expressed during the course of a human's normal life cycle. Sometimes, these genes are inappropriately expressed at an inopportune time because of a genetic defect of an individual or because an individual may have been exposed to a chemical or physical agent, either accidentally or purposefully, that induces toxicity or some pathology in that individual. The inappropriate expression of a gene or set of genes may result in cancer, heart or blood vessel disease, a behavioral change, or some other adverse event.

The study of thousands of genes at a time requires the use of another discipline called bioinformatics. This scientific discipline encompasses computer science and engineering, statistics, and mathematics. The necessary bioinformatic tools include a repository for the large amounts of data developed, a database; tools to analyze and visualize the data in a format that is familiar to the scientist developing the hypothesis; and tools to help the scientist interpret that information stored in the database. Ideally, the database is available to any interested party and is public; however, in some instances, the data are proprietary, such as the data assessed by the FDA, and, therefore, not available to the public.

The new technologies discussed in this issue of FDA Consumer are being used in a variety of different scientific disciplines including the discipline of toxicology, which attempts to understand how adverse events are induced in organisms as a function of exposure to potential toxic substances or poisons. The term toxicogenomics is used to describe a new subdiscipline of toxicology that combines the emerging technologies of functional and structural genomics, proteomics, and bioinformatics to address biological or toxicological problems and to identify and characterize the action of known or suspected toxic substances.

About the Author

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FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.